title: Synthesis of neurotransmitter GABA via the neuronal tricarboxylic acid cycle is elevated in rats with liver cirrhosis consistent with a high GABAergic tone in chronic hepatic encephalopathy.
abstract: Hepatic encephalopathy (HE) is a neuropsychiatric complication to liver disease. It is known that ammonia plays a role in the pathogenesis of HE and disturbances in the GABAergic system have been related to HE. Synthesis of GABA occurs by decarboxylation of glutamate formed by deamidation of astrocyte-derived glutamine. It is known that a fraction of glutamate is decarboxylated directly to GABA (referred to as the direct pathway) and that a fraction undergoes transamination with formation of alpha-ketoglutarate. The latter fraction is cycled through the neuronal tricarboxylic acid cycle, an energy-generating pathway, prior to being employed for GABA synthesis (the indirect pathway). We have previously shown that ammonia induces an elevation of the neuronal tricarboxylic acid cycle activity. Thus, the aims of the present study were to determine if increased levels of ammonia increase GABA synthesis via the indirect pathway in a rat model of HE induced by bile-duct ligation and in co-cultures of neurons and astrocytes exposed to ammonia. Employing (13) C-labeled precursors and subsequent analysis by mass spectrometry, we demonstrated that more GABA was synthesized via the indirect pathway in bile duct-ligated rats and in co-cultures subjected to elevated ammonia levels. Since the indirect pathway is associated with synthesis of vesicular GABA, this might explain the increased GABAergic tone in HE.
authors.affiliation: PET Centre, Department of Medicine V, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Renata
authors.initials: R
authors.lastname: Leke
authors.forename: Lasse K
authors.initials: LK
authors.lastname: Bak
authors.forename: Peter
authors.initials: P
authors.lastname: Iversen
authors.forename: Michael
authors.initials: M
authors.lastname: Sørensen
authors.forename: Susanne
authors.initials: S
authors.lastname: Keiding
authors.forename: Hendrik
authors.initials: H
authors.lastname: Vilstrup
authors.forename: Peter
authors.initials: P
authors.lastname: Ott
authors.forename: Luis V
authors.initials: LV
authors.lastname: Portela
authors.forename: Arne
authors.initials: A
authors.lastname: Schousboe
authors.forename: Helle S
authors.initials: HS
authors.lastname: Waagepetersen
mesh_terms: D000085:Acetates / Q000378:metabolism; D000641:Ammonia / Q000097:blood; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001923:Brain Chemistry / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D002908:Chronic Disease; D002952:Citric Acid Cycle / Q000502:physiology*; D018920:Coculture Techniques; D003135:Common Bile Duct / Q000502:physiology; D018846:Excitatory Amino Acids; D005260:Female; D006501:Hepatic Encephalopathy / Q000378:metabolism*; D008026:Ligation; D008103:Liver Cirrhosis / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis* / Q000502:physiology*
chemical_list: D000085:Acetates; D018846:Excitatory Amino Acids; D018377:Neurotransmitter Agents; D005680:gamma-Aminobutyric Acid; D000641:Ammonia